P4HA2

Summary

P4HA2 (prolyl 4-hydroxylase subunit alpha 2, HGNC:8547) is a protein-coding gene on chromosome 5q31.1, encoding Prolyl 4-hydroxylase subunit alpha-2 (O15460). Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.

This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 8974 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopia (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 16
• Clinical variants (ClinVar): 141 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 73
• Druggable target: yes
• MANE Select transcript: NM_001017974

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8547
Approved symbol	P4HA2
Name	prolyl 4-hydroxylase subunit alpha 2
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	C-P4Halpha(II), lncRNA-PE
Ensembl gene	ENSG00000072682
Ensembl biotype	protein_coding
OMIM	600608
Entrez	8974

Gene structure

Transcript identifiers

Ensembl transcripts: 75 — 69 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000166534, ENST00000360568, ENST00000379086, ENST00000379100, ENST00000379104, ENST00000395164, ENST00000401867, ENST00000416053, ENST00000417528, ENST00000418055, ENST00000428369, ENST00000428841, ENST00000431054, ENST00000439698, ENST00000453286, ENST00000467587, ENST00000471826, ENST00000474628, ENST00000478055, ENST00000481636, ENST00000506807, ENST00000889324, ENST00000889325, ENST00000889326, ENST00000889327, ENST00000889328, ENST00000889329, ENST00000889330, ENST00000889331, ENST00000889332, ENST00000889333, ENST00000889334, ENST00000889335, ENST00000889336, ENST00000889337, ENST00000889338, ENST00000889339, ENST00000889340, ENST00000889341, ENST00000889342, ENST00000889343, ENST00000889344, ENST00000889345, ENST00000889346, ENST00000889347, ENST00000889348, ENST00000889349, ENST00000889350, ENST00000889351, ENST00000889352, ENST00000889353, ENST00000889354, ENST00000889355, ENST00000889356, ENST00000889357, ENST00000889358, ENST00000944792, ENST00000944793, ENST00000944794, ENST00000944795, ENST00000944796, ENST00000944797, ENST00000944798, ENST00000944799, ENST00000944800, ENST00000944801, ENST00000944802, ENST00000944803, ENST00000944804, ENST00000944805, ENST00000944806, ENST00000944807, ENST00000944808, ENST00000944809, ENST00000944810

RefSeq mRNA: 9 — MANE Select: NM_001017974 NM_001017974, NM_001142598, NM_001142599, NM_001365677, NM_001365678, NM_001365679, NM_001365680, NM_001365681, NM_004199

CCDS: CCDS34230, CCDS4151

Canonical transcript exons

ENST00000360568 — 15 exons

Exon	Start	End
ENSE00000899283	132217752	132217848
ENSE00001084069	132198879	132198932
ENSE00001084071	132203748	132203847
ENSE00001084073	132204082	132204152
ENSE00001084075	132195412	132195480
ENSE00001387195	132198321	132198380
ENSE00001898471	132227790	132227853
ENSE00003241079	132207708	132207884
ENSE00003387808	132209138	132209331
ENSE00003406585	132213916	132214053
ENSE00003443962	132217197	132217348
ENSE00003447053	132210284	132210523
ENSE00003544598	132194926	132195022
ENSE00003578294	132218545	132218644
ENSE00003906851	132190147	132193080

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 98.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.1263 / max 650.7626, expressed in 1734 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63302	23.4224	1629
63301	1.8068	789
63300	1.0836	542
63305	0.8235	112
63304	0.3211	76
63299	0.2224	118
63306	0.1839	66
63307	0.0779	17
63297	0.0767	40
63308	0.0669	22

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.95	gold quality
tibia	UBERON:0000979	98.12	gold quality
body of pancreas	UBERON:0001150	97.29	gold quality
islet of Langerhans	UBERON:0000006	96.65	gold quality
pancreas	UBERON:0001264	96.10	gold quality
bronchial epithelial cell	CL:0002328	95.45	gold quality
cartilage tissue	UBERON:0002418	95.20	gold quality
apex of heart	UBERON:0002098	94.98	gold quality
smooth muscle tissue	UBERON:0001135	94.90	gold quality
right atrium auricular region	UBERON:0006631	94.64	gold quality
corpus epididymis	UBERON:0004359	94.51	gold quality
cardiac atrium	UBERON:0002081	93.93	gold quality
ascending aorta	UBERON:0001496	93.90	gold quality
mucosa of transverse colon	UBERON:0004991	93.90	gold quality
periodontal ligament	UBERON:0008266	93.73	gold quality
thoracic aorta	UBERON:0001515	93.67	gold quality
pituitary gland	UBERON:0000007	93.59	gold quality
germinal epithelium of ovary	UBERON:0001304	93.57	gold quality
heart left ventricle	UBERON:0002084	93.57	gold quality
body of uterus	UBERON:0009853	93.54	gold quality
adenohypophysis	UBERON:0002196	93.46	gold quality
cardiac ventricle	UBERON:0002082	93.36	gold quality
lower esophagus mucosa	UBERON:0035834	93.31	gold quality
epithelium of bronchus	UBERON:0002031	93.16	gold quality
left uterine tube	UBERON:0001303	93.09	gold quality
skin of hip	UBERON:0001554	93.08	gold quality
heart	UBERON:0000948	92.91	gold quality
parietal pleura	UBERON:0002400	92.84	gold quality
bronchus	UBERON:0002185	92.78	gold quality
rectum	UBERON:0001052	92.77	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	39.30
E-ANND-3	yes	16.45
E-MTAB-9067	yes	14.56
E-MTAB-6678	yes	3.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

54 targeting P4HA2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4492	99.87	68.25	3611

Literature-anchored findings (GeneRIF, showing 28)

• the substrate specificity, binding site and conformation of this enzyme (PMID:12824157)
• In comparison with healthy cartilage, Osteoarthritis articular chondrocytes exhibit increased in vivo synthesis of collagen prolyl-4-hydroxylase type II, a pivotal enzyme in collagen triple helix formation. (PMID:16877351)
• HIF-P4H, HIF-1alpha and HIF-2alpha are effective oxygen sensors (PMID:16885164)
• results show that p53 transcriptionally activates the alpha(II) collagen prolyl-4-hydroxylase [alpha(II)PH] gene, resulting in the extracellular release of antiangiogenic fragments of collagen type 4 and 18 (PMID:16917063)
• Overexpression of PRDX4 and P4HA2 was significantly associated with lymphatic metastasis in oral cavity squamous cell carcinoma (PMID:21859152)
• P4HA2 was upregulated in breast tumor cells compared with its adjacent normal tissues. (PMID:22813596)
• Suggest the critical role of P4HA2 in breast cancer progression and identify P4HA2 as a potential therapeutic target and biomarker for breast cancer progression. (PMID:24383403)
• P4HA2 was identified as a novel causative gene for nonsyndromic high myopia. (PMID:25741866)
• RNAsequencing showed that the t(4;5)(q24;q31) resulted in recombination of the genes TBCK on 4q24 and P4HA2 on 5q31.1 with generation of an inframe TBCKP4HA2 and the reciprocal but outofframe P4HA2TBCK fusion transcripts. (PMID:27633981)
• Plasminogen and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis (PMID:28041642)
• Assembly of the elongated collagen prolyl 4-hydroxylase alpha2beta2 heterotetramer around a central alapha2 dimer has been reported. (PMID:28093469)
• This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations (PMID:29364500)
• identify prolyl 4-hydroxylase 2 (P4HA2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/extracellular signal-regulated kinase pathway and increasing B-cell lymphoma proliferation. (PMID:29437589)
• P4HA2 plays a role in ductal carcinoma in situ (DCIS) progression and can potentially be used to predict DCIS outcome. (PMID:30410060)
• The data show that a low P4HA2 and high PRTN3 expression correlates with poor survival in patients with pancreatic cancer, indicating the involvement of collagen deposition in the restraint of the tumor. (PMID:30880498)
• lncRNA LMCD1-AS1 functions as a molecular sponge of let-7g to post-transcriptionally induce the target gene of let-7g, namely, P4HA2 (PMID:31278071)
• LncRNA PCGEM1 enhances metastasis and gastric cancer invasion through targeting of miR-129-5p to regulate P4HA2 expression. (PMID:32622013)
• Targeting HIF-activated collagen prolyl 4-hydroxylase expression disrupts collagen deposition and blocks primary and metastatic uveal melanoma growth. (PMID:34218269)
• Prognostic and diagnostic roles of prolyl 4-hydroxylase subunit alpha members in breast cancer. (PMID:34387118)
• P4HA2-induced prolyl hydroxylation suppresses YAP1-mediated prostate cancer cell migration, invasion, and metastasis. (PMID:34471235)
• [P4HA2 promotes occurrence and progression of liver cancer by regulating the PI3K/Akt/mTOR signaling pathway]. (PMID:35673909)
• High expression of prolyl 4-hydroxylase subunit alpha-2 in lung adenocarcinoma indicates poor prognosis. (PMID:36403427)
• CEBPB upregulates P4HA2 to promote the malignant biological behavior in IDH1 wildtype glioma. (PMID:36906285)
• P4HA2-mediated HIF-1alpha stabilization promotes erdafitinib-resistance in FGFR3-alteration bladder cancer. (PMID:36943397)
• P4HA2 involved in SLUG-associated EMT predicts poor prognosis of patients with KRAS-positive colorectal cancer. (PMID:38522060)
• P4HA2 contributes to head and neck squamous cell carcinoma progression and EMT through PI3K/AKT signaling pathway. (PMID:38777998)
• P4HA2 promotes tumor progression and is transcriptionally regulated by SP1 in colorectal cancer. (PMID:38857058)
• P4HA2 promotes proliferation, invasion, and metastasis through regulation of the PI3K/AKT signaling pathway in oral squamous cell carcinoma. (PMID:38951593)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	p4ha2	ENSDARG00000010085
mus_musculus	P4ha2	ENSMUSG00000018906
rattus_norvegicus	P4ha2	ENSRNOG00000033663
drosophila_melanogaster	CG31021	FBGN0051021
caenorhabditis_elegans		WBGENE00004026
caenorhabditis_elegans		WBGENE00015773
caenorhabditis_elegans		WBGENE00077688

Paralogs (3): P4HA1 (ENSG00000122884), P4HA3 (ENSG00000149380), P4HTM (ENSG00000178467)

Protein

Protein identifiers

Prolyl 4-hydroxylase subunit alpha-2 — O15460 (reviewed: O15460)

Alternative names: Procollagen-proline,2-oxoglutarate-4-dioxygenase subunit alpha-2

All UniProt accessions (10): O15460, A8MXE0, C9JCP0, C9JFJ1, C9JIG4, C9JN43, C9JX45, E7ENX0, E7EPI9, E7ERI1

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.

Subunit / interactions. Heterotetramer of two alpha-2 chains and two beta chains (P4HB) (the beta chain is the multi-functional PDI), where P4HB plays the role of a structural subunit; this tetramer catalyzes the formation of 4-hydroxyproline in collagen.

Subcellular location. Endoplasmic reticulum lumen.

Tissue specificity. Expressed in the heart, placenta, lung and pancreas.

Disease relevance. Myopia 25, autosomal dominant (MYP25) [MIM:617238] A refractive error of the eye, in which parallel rays from a distant object come to focus in front of the retina, vision being better for near objects than for far. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by poly(L-proline) only at very high concentrations.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Similarity. Belongs to the P4HA family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15460-1	IIb	yes
O15460-2	IIa

RefSeq proteins (9): NP_001017974, NP_001136070, NP_001136071, NP_001352606, NP_001352607, NP_001352608, NP_001352609, NP_001352610, NP_004190 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005123	Oxoglu/Fe-dep_dioxygenase_dom	Domain
IPR006620	Pro_4_hyd_alph	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR013547	P4H_N	Domain
IPR019734	TPR_rpt	Repeat
IPR044862	Pro_4_hyd_alph_FE2OG_OXY	Domain
IPR045054	P4HA-like	Family
IPR059068	TPR_P4H	Domain

Pfam: PF08336, PF13640, PF23558

Enzyme classification (BRENDA):

• EC 1.14.11.2 — procollagen-proline 4-dioxygenase (BRENDA: 37 organisms, 182 substrates, 264 inhibitors, 251 Km, 44 kcat entries)

Substrate kinetics (BRENDA)

77 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.001–1	37
POLY(L-PROLINE)	0.0002–1.59	26
(L-PRO-L-PRO-GLY)10	0.015–2.9	15
(PRO-PRO-GLY)10	0.011–1.27	15
POLY(L-PRO)	0.002–0.65	15
FE2+	0.0004–0.016	9
O2	0.03–1.5	9
ASCORBATE	0.14–0.37	8
(L-PRO-L-PRO-GLY)5	0.12–1.8	6
PROTOCOLLAGEN	—	6
(L-PRO-L-ALA-L-PRO-L-LYS)3	0.09–0.31	4
(SER-PRO)5	0.14–0.78	4
DLDLEMLAPYIPMDD	0.009–0.1	3
DLDLEMLAPYIPMDDDF	0.007–0.07	3
EMLAPYIPMDDDFQL	0.007–0.08	3

Catalyzed reactions (Rhea), 1 shown:

• L-prolyl-[collagen] + 2-oxoglutarate + O2 = trans-4-hydroxy-L-prolyl-[collagen] + succinate + CO2 (RHEA:18945)

UniProt features (20 total): helix 5, binding site 4, sequence variant 3, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, repeat 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6EVN	X-RAY DIFFRACTION	1.48
6EVO	X-RAY DIFFRACTION	1.55
6EVP	X-RAY DIFFRACTION	1.68
9HTD	X-RAY DIFFRACTION	1.75
6EVL	X-RAY DIFFRACTION	1.87
6EVM	X-RAY DIFFRACTION	2
7ZSC	X-RAY DIFFRACTION	3.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15460-F1	89.63	0.72

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 430; 432; 501; 511

Post-translational modifications (1): 480

Glycosylation sites (2): 264, 115

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-9918432	Maturation of DENV proteins

MSigDB gene sets: 397 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, MENSE_HYPOXIA_UP, MODULE_478, GTGCCTT_MIR506, MISSIAGLIA_REGULATED_BY_METHYLATION_UP, SEMENZA_HIF1_TARGETS, MODULE_75, ONKEN_UVEAL_MELANOMA_UP, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, WINTER_HYPOXIA_METAGENE, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P

GO Biological Process (0):

GO Molecular Function (9): procollagen-proline 4-dioxygenase activity (GO:0004656), iron ion binding (GO:0005506), electron transfer activity (GO:0009055), L-ascorbic acid binding (GO:0031418), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (4): nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Collagen formation	1
Dengue Virus Genome Translation and Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity	2
cellular anatomical structure	2
cytoplasm	2
procollagen-proline dioxygenase activity	1
peptidyl-proline 4-dioxygenase activity	1
transition metal ion binding	1
molecular_function	1
vitamin binding	1
carboxylic acid binding	1
monosaccharide binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
P4HA2	P4HB	P07237	974
P4HA2	PLOD1	Q02809	887
P4HA2	P3H2	Q8IVL5	886
P4HA2	P3H1	Q32P28	810
P4HA2	PLOD2	O00469	804
P4HA2	PDIA3	P30101	779
P4HA2	PDIA4	P13667	779
P4HA2	EGLN1	Q9GZT9	724
P4HA2	HIF1A	Q16665	685
P4HA2	SLC22A5	O76082	665
P4HA2	EGLN3	Q9H6Z9	650
P4HA2	DCK	P27707	650
P4HA2	PLOD3	O60568	638
P4HA2	ARNT	P27540	630
P4HA2	EGLN2	Q96KS0	616

IntAct

62 interactions, top by confidence:

A	B	Type	Score
P4HA2	P4HB	psi-mi:“MI:0915”(physical association)	0.740
P4HB	P4HA2	psi-mi:“MI:0914”(association)	0.740
P4HA2	P4HB	psi-mi:“MI:0914”(association)	0.740
CCT2	TXNDC9	psi-mi:“MI:0914”(association)	0.730
COL1A1	P4HA2	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
KIF7	P4HA2	psi-mi:“MI:0915”(physical association)	0.670
CCT7	TXNDC9	psi-mi:“MI:0914”(association)	0.640
KLHL9	ENC1	psi-mi:“MI:0914”(association)	0.640
IRS4	PIK3R2	psi-mi:“MI:0914”(association)	0.640
P4HA1	P4HA2	psi-mi:“MI:0915”(physical association)	0.560
EBNA-LP	HAX1	psi-mi:“MI:0914”(association)	0.530
ZNF397	ZNF197	psi-mi:“MI:0914”(association)	0.530
TIGD5	P4HA2	psi-mi:“MI:0914”(association)	0.530
NEK7	P4HA2	psi-mi:“MI:0914”(association)	0.510
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
env	PSMD11	psi-mi:“MI:0914”(association)	0.460
ALK	PIK3R2	psi-mi:“MI:0914”(association)	0.420
PPIC	P4HA2	psi-mi:“MI:0915”(physical association)	0.400
RPS13	P4HA2	psi-mi:“MI:0915”(physical association)	0.400
VPS13D	P4HA2	psi-mi:“MI:0915”(physical association)	0.400
UTP3	P4HA2	psi-mi:“MI:0915”(physical association)	0.400
MORC2	P4HA2	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
P4HA2	CREB3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (181): P4HA2 (Two-hybrid), P4HA2 (Affinity Capture-MS), P4HA2 (Affinity Capture-MS), P4HA2 (Affinity Capture-MS), P4HA2 (Co-fractionation), PPL (Co-fractionation), P4HA2 (Two-hybrid), P4HA2 (Two-hybrid), P4HA2 (Two-hybrid), P4HA2 (Affinity Capture-MS), P4HA2 (Affinity Capture-MS), P4HA2 (Affinity Capture-MS), P4HA2 (Affinity Capture-MS), P4HA2 (Affinity Capture-MS), P4HA2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B5GR44, A0A166YZY4, A7XDQ9, F4HSU3, F4ILF8, F4KF16, O04084, O15460, O23364, P13674, P16924, P43295, P54001, Q0WRX3, Q0WUG6, Q10576, Q16820, Q1PFD9, Q1RMU3, Q4V398, Q5RAG8, Q5UP57, Q5ZLK5, Q60715, Q60716, Q6E279, Q6W3E9, Q84LR6, Q84WF0, Q8GXT7, Q8L7B2, Q8LED3, Q8LPF8, Q8RXQ1, Q8VZJ7, Q8VZU3, Q93ZR8, Q9C7Z9, Q9CAU0, Q9LSV8

Diamond homologs: F4ILF8, F4J0A8, F4JAU3, F4JNU8, F4JZ24, O15460, P0DUB0, P13674, P16924, P54001, Q10576, Q19673, Q1RMU3, Q20065, Q24JN5, Q5RAG8, Q5UP57, Q5ZLK5, Q60715, Q60716, Q6W3E9, Q6W3F0, Q75UG4, Q7Z4N8, Q8BG58, Q8GXT7, Q8L970, Q8LAN3, Q8VZJ7, Q9LN20, Q9NXG6, Q9SZT0, Q9ZW86

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
P4HA2	“up-regulates quantity by stabilization”	Collagen	hydroxylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 71 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Collagen biosynthesis and modifying enzymes	6	21.3×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

141 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	97
Likely benign	18
Benign	3

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
372166	NM_001017974.2(P4HA2):c.419A>G (p.Gln140Arg)	Pathogenic
372167	NM_001365677.2(P4HA2):c.1352_1353del (p.Val451fs)	Pathogenic
4082191	NM_001017974.2(P4HA2):c.601G>C (p.Glu201Gln)	Likely pathogenic
4082194	NM_001017974.2(P4HA2):c.751G>A (p.Glu251Lys)	Likely pathogenic

SpliceAI

4100 predictions. Top by Δscore:

Variant	Effect	Δscore
5:132193081:C:CC	acceptor_gain	1.0000
5:132194925:CCCCA:C	donor_gain	1.0000
5:132195021:CC:C	acceptor_gain	1.0000
5:132195022:CC:C	acceptor_gain	1.0000
5:132195022:CCT:C	acceptor_loss	1.0000
5:132195023:C:CA	acceptor_loss	1.0000
5:132195023:C:CC	acceptor_gain	1.0000
5:132195407:CTTA:C	donor_loss	1.0000
5:132195408:TTACC:T	donor_loss	1.0000
5:132195409:TACCT:T	donor_loss	1.0000
5:132195410:A:T	donor_loss	1.0000
5:132195411:C:CG	donor_loss	1.0000
5:132204077:CTTA:C	donor_loss	1.0000
5:132204079:TACCT:T	donor_loss	1.0000
5:132204149:CAAG:C	acceptor_gain	1.0000
5:132204150:AAG:A	acceptor_gain	1.0000
5:132204151:AG:A	acceptor_gain	1.0000
5:132204153:C:CC	acceptor_gain	1.0000
5:132207702:ACCT:A	donor_loss	1.0000
5:132207705:TA:T	donor_loss	1.0000
5:132207706:A:AC	donor_gain	1.0000
5:132207706:AC:A	donor_loss	1.0000
5:132207707:C:CC	donor_gain	1.0000
5:132207707:C:CT	donor_loss	1.0000
5:132209178:T:TA	donor_gain	1.0000
5:132209212:AGATG:A	donor_gain	1.0000
5:132210278:CCTTA:C	donor_loss	1.0000
5:132210280:TTACC:T	donor_loss	1.0000
5:132210283:CCA:C	donor_loss	1.0000
5:132217193:TCACC:T	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000018012 (5:132205681 CTG>C), RS1000050963 (5:132212502 T>C), RS1000096069 (5:132199733 C>A), RS1000110015 (5:132219860 A>G), RS1000127261 (5:132227674 A>C,G), RS1000196486 (5:132194555 G>A,C), RS1000292623 (5:132191385 G>A,C), RS1000311058 (5:132194310 C>T), RS1000421409 (5:132191662 C>G), RS1000503656 (5:132207844 T>C,G), RS1000593089 (5:132210581 A>T), RS1000615128 (5:132214289 G>A,C), RS1000713188 (5:132201134 G>A), RS1000723507 (5:132208125 T>C), RS1000850372 (5:132227877 C>T)

Disease associations

OMIM: gene MIM:600608 | disease phenotypes: MIM:617238

GenCC curated gene-disease

Disease	Classification	Inheritance
myopia	Strong	Autosomal dominant
myopia 25, autosomal dominant	Limited	Autosomal dominant

Mondo (2): myopia 25, autosomal dominant (MONDO:0014982), myopia (MONDO:0001384)

Orphanet (0):

HPO phenotypes

73 total (30 of 73 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000083	Renal insufficiency
HP:0000206	Glossitis
HP:0000365	Hearing impairment
HP:0000405	Conductive hearing impairment
HP:0000421	Epistaxis
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000541	Retinal detachment
HP:0000572	Visual loss
HP:0000597	Ophthalmoparesis
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000651	Diplopia
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000873	Diabetes insipidus
HP:0000975	Hyperhidrosis
HP:0001123	Visual field defect
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001287	Meningitis
HP:0001324	Muscle weakness
HP:0001369	Arthritis
HP:0001387	Joint stiffness
HP:0001399	Hepatic failure
HP:0001596	Alopecia
HP:0001645	Sudden cardiac death
HP:0001701	Pericarditis
HP:0001824	Weight loss

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001438_16	Crohn’s disease	4.000000e-08
GCST003928_4	Giant cell arteritis	5.000000e-09
GCST004131_32	Inflammatory bowel disease	4.000000e-27
GCST004132_10	Crohn’s disease	6.000000e-36
GCST004133_36	Ulcerative colitis	2.000000e-06
GCST004624_88	Sum eosinophil basophil counts	5.000000e-15
GCST005580_165	Intraocular pressure	1.000000e-08
GCST007564_20	Asthma or allergic disease (pleiotropy)	5.000000e-10
GCST008163_162	Height	7.000000e-08
GCST008916_106	Asthma	2.000000e-25
GCST010701_41	Cortical surface area (MOSTest)	1.000000e-20
GCST010702_96	Subcortical volume (MOSTest)	2.000000e-08
GCST010703_160	Brain morphology (MOSTest)	3.000000e-09
GCST011011_46	Youthful appearance (self-reported)	6.000000e-10
GCST011020_2	Intracranial aneurysm	3.000000e-10
GCST011021_2	Intracranial aneurysm	3.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0004695	intraocular pressure measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009216	Myopia	C11.744.636

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5640 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

65 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression, affects expression	7
bisphenol A	affects expression, decreases expression, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression, affects cotreatment	3
cobaltous chloride	increases expression, decreases reaction	3
Cisplatin	decreases response to substance, affects expression, affects cotreatment, increases expression	3
entinostat	increases expression, affects cotreatment	2
bisphenol S	affects expression, increases expression	2
Decitabine	affects expression, increases expression	2
Acetaminophen	increases expression	2
Ethanol	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Estradiol	decreases expression, increases expression, affects cotreatment	2
Oxygen	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases methylation	2
bisphenol F	increases expression	1
lead acetate	affects cotreatment, decreases expression	1
zinc chloride	increases expression, decreases reaction	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	increases expression, increases abundance	1
1,10-phenanthroline	increases expression	1
nickel sulfate	increases expression	1
chromium hexavalent ion	increases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1058918	Binding	Inhibition of prolyl-4-hydroxylase 2	HIF-1alpha peptide derivatives with modifications at the hydroxyproline residue as activators of HIF-1alpha. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C3RE	WAe009-A-J	Embryonic stem cell	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00347204	PHASE4	COMPLETED	Comparison of Acular LS Versus Nevanac for Pain Control in Eyes Undergoing PRK
NCT00349843	PHASE4	COMPLETED	Investigation of Multi-Purpose Solution-Based Corneal Staining and Ocular Comfort
NCT00349882	PHASE4	COMPLETED	Effects of Contact Lens Care Regimens on the Corneal Epithelium
NCT00350246	PHASE4	COMPLETED	Long-term Effects of Laser Refractive Surgery
NCT00404105	PHASE4	COMPLETED	A Comparison of PRK and LASIK for Correction of Myopia
NCT00455455	PHASE4	COMPLETED	Corneal and Conjunctival Sensitivity and Staining Study
NCT00541177	PHASE4	UNKNOWN	Study of Myopia Prevention in Children With Low Concentration of Atropine
NCT00627302	PHASE4	COMPLETED	Efficacy of PEG-400 and Systane Artificial Tears (Alcon) on Quality of Vision
NCT00640341	PHASE4	COMPLETED	Comparative Performance of PureVision, Acuvue Oasys and O2Optix
NCT00770094	PHASE4	UNKNOWN	Multi Laser Platform Comparison Study for LASIK
NCT00821236	PHASE4	COMPLETED	Contralateral Comparison of Three Excimer Laser Systems in Performing LASIK
NCT00889941	PHASE4	COMPLETED	Effect of Preoperative Pupil Size on Quality of Vision After Wavefront-Guided LASIK
NCT00937105	PHASE4	COMPLETED	Daily Wear Corneal Infiltrative Event Study
NCT01173198	PHASE4	COMPLETED	An Evaluation of Outcomes Following Wavefront Optimized or Wavefront Guided Lasik Procedure in Low to Moderate Myopic Patients
NCT01250925	PHASE4	COMPLETED	Effect of Contact Lens Wear on Immune Cell Density and Morphology of the Ocular Surface
NCT01387360	PHASE4	COMPLETED	Presbyopic Supracor Treatment for Near Myopic/Hyperopic Pseudophakic Eyes
NCT01454843	PHASE4	COMPLETED	LASIK Using the Alcon Allegretto Wavefront-Guided Excimer Laser vs AMO Visx Wavefront-Guided Excimer Laser
NCT01693939	PHASE4	COMPLETED	Evaluation of the Post-LASIK Flap Thickness of the FS200 Femtosecond Laser Flap
NCT01706237	PHASE4	WITHDRAWN	Visual Outcomes And Contrast Sensitivity After Myopic Wavefront-Optimized Lasik With Nexisvision Shield Or Bandage Contact Lens
NCT01746589	PHASE4	COMPLETED	Visual Outcomes and Contrast Sensitivity After Myopic LASIK
NCT01977807	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser in Asian Eyes Using LASIK
NCT02071576	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser Using LASIK
NCT02112968	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of a New High Repetition Rate Excimer Laser Using LASIK for the Correction of Ammetropia and Presbyopia
NCT02186184	PHASE4	COMPLETED	Effect of Orthokeratology Versus Spectacles on Myopia Progression in Chinese Children: A Crossover Trial
NCT02544529	PHASE4	WITHDRAWN	Echothiophate Iodide for the Prevention of Progression of Myopia
NCT03001401	PHASE4	UNKNOWN	Comparison of Next Generation Laser Techniques of Myopia Correction: iDesign vs. SMILE
NCT03158142	PHASE4	COMPLETED	The Influence of Atropine on Choroidal Thickness
NCT03544827	PHASE4	COMPLETED	The Effects of Low Dose Atropine on Choroidal Thickness
NCT03881670	PHASE4	COMPLETED	On-Eye Optical Quality of Lotrafilcon B Lenses Over 12 Hours
NCT03949101	PHASE4	UNKNOWN	Atropine for Children and Adolescent Myopia Progression Study
NCT04208750	PHASE4	COMPLETED	Clinical Investigation of the Vision-R800 Device.
NCT04283331	PHASE4	UNKNOWN	Anesthetic Impregnated Bandage Soft Contact Lens (BSCL) in Pain Management After Photorefractive Keratectomy (PRK)
NCT05357326	PHASE4	UNKNOWN	Myopia Intervention in Children and Adolescents and Establishment of a Precise Intervention Model
NCT05448989	PHASE4	UNKNOWN	Efficacy and Safety of 1% Atropine 5+3 Regimen in Children and Adolescents Controlling Myopia
NCT05449015	PHASE4	UNKNOWN	Study on the Effect of Two Ways of Cycloplegia on Biological Parameters of Ciliary Muscle
NCT05733741	PHASE4	COMPLETED	Preservative-free Topical Anesthetics for Post-PRK Pain
NCT05803863	PHASE4	UNKNOWN	Efficacy Comparison of 2 Low-dose Atropine Eye Drops in Vietnamese Children Myopia Management
NCT06431841	PHASE4	ACTIVE_NOT_RECRUITING	Atropine and Spectacle Combination Treatment (ASPECT): 12-month Results of a Randomized Clinical Trial for Myopia Control
NCT06450132	PHASE4	ACTIVE_NOT_RECRUITING	Changes in Eye Shape With Myopia Management Interventions
NCT06553404	PHASE4	ACTIVE_NOT_RECRUITING	Myoslow Lens Study to Control Myopia in Children